ABSTRACT

The work of this PhD dissertation was primarily carried out at Department for Tumour Endocrinology, Danish Cancer Society. The dissertation consists of one published paper, two submitted manuscripts, one manuscript in prep and one paper in press.

The aim of the present study was to investigate which proteins and genes were differentially expressed between antiestrogen sensitive and resistant human breast cancer cell lines. For this purpose Atlas ArrayTM and real-time RT-PCR screening of the gene expression were carried out, and for elucidation of whether dominant or recessive mechanisms are involved in development of antioestrogen resistance, cell fusion was performed. Finally, more detailed studies of selected proteins and genes were carried out.

Real-time RT-PCR was found to be a useful method for multi-parametric RNA analysis. Our data indicate that ER α , PR, EGFR and ErbB-2 could be involved, whereas, ER α , AIB1, BCAR1, CYP19 and MDR1 are probably not involved in development of antioestrogen resistance. Cell fusion studies showed that antioestrogen resistance is neither caused by purely dominant or recessive genetical alterations, but rather represents a multi-factoriel process. Furthermore, it was shown that different mechanisms are involved in development of resistance to different types of antioestorgens, which is promising in relation to sequential treatment of breast cancer patients. Our investigations showed that increased expression of CYP1A1 and CYP1B1 does not cause conversion of the antioestrogen ICI 182780 (FaslodexTM) to less active compounds. Finally, we found that PKB/Akt1 and IGFBP2 might be involved in development of resistance to tamoxifen and ICI 182780.

Overall, this study contributes with new information about the molecular alterations, which might lead to development of resistance to antioestrogen treatment in breast cancer.